Synonyms of Pantothenate Kinase-Associated Neurodegeneration

General Discussion

Summary

Pantothenate kinase-associated neurodegeneration (PKAN), formerly called Hallervorden-Spatz syndrome, is a rare, inherited neurological movement disorder characterized by the progressive degeneration of specific regions in the central nervous system (neurodegenerative disorder). PKAN is the most common type of neurodegeneration with brain iron accumulation (NBIA), a group of clinical disorders marked by progressive abnormal involuntary movements, alterations in muscle tone, and postural disturbances (extrapyramidal). These disorders show radiographic evidence of iron accumulation in the brain. PKAN is typically diagnosed by molecular genetic testing, most often after a characteristic finding on magnetic resonance imaging (MRI), called the “eye-of-the-tiger” sign, is detected.

PKAN is inherited as an autosomal recessive genetic condition and is described as being classical or atypical. Classic PKAN typically appears in early childhood with symptoms that worsen rapidly. Atypical PKAN, which progresses more slowly, appears later in childhood or early adolescence. Some people have been diagnosed in infancy or adulthood, and some of those affected have characteristics that are between the two categories.

Introduction

Hallervorden-Spatz syndrome was first described in 1922 by Drs. Julius Hallervorden and Hugo Spatz with their study of a family of 12 in which five sisters exhibited progressively increasing dementia and poor articulation and slurred speech (dysarthria). The name Hallervorden-Spatz syndrome became discouraged and was replaced with neurodegeneration with brain iron accumulation because of concerns regarding Dr. Hallervorden’s and Dr. Spatz’s affiliation with the Nazi regime and their unethical activities surrounding how they obtained many autopsy specimens.

Signs & Symptoms

The common feature among all individuals with PKAN is iron accumulation in the brain, in a pattern called the ‘eye of the tiger sign,’ along with a progressive movement disorder. Symptoms may vary greatly from case to case. In most cases, progression of the disease extends over several years, leading to death in childhood or early adulthood in classic cases. Some patients experience rapid deterioration and die within 1-2 years. Others have a slower progression or can plateau for long periods of time and continue to function into the third decade of life. Atypical individuals often retain a high level of function into later adulthood and some are known to be living in their sixties to seventies.

Dystonia is characterized by involuntary muscle contractions that may force certain body parts into unusual, and sometimes painful, movements and positions. In addition, there may be stiffness in the arms and legs because of continuous resistance to muscle relaxing (spasticity) and abnormal tightening of the muscles (muscular rigidity). Spasticity and muscle rigidity usually begin in the legs and later develop in the arms. As affected individuals age, they may eventually lose control of voluntary movements. Muscle spasms combined with decreased bone mass can result in bone fractures (not caused by trauma or accident).

Dystonia affects the muscles in the mouth and throat, which may cause dysarthria and difficulty swallowing (dysphagia). The progression of dystonia in these muscles can result in loss of speech as well as tongue-biting and difficulty with eating.

Specific forms of dystonia that may occur in association with PKAN include blepharospasm and torticollis. Blepharospasm is a condition in which the muscles of the eyelids do not function properly, resulting in excessive blinking and involuntary closing of the eyelids. Torticollis is a condition in which there are involuntary contractions of neck muscles resulting in abnormal movements and positions of the head and neck.
Many of the delays in development pertain to motor skills (movement), although a small subgroup may have intellectual delays. Although intellectual impairment has often been described as a part of the condition in the past, it is unclear if this is a true feature. Intellectual testing may be hampered by the movement disorder; therefore, newer methods of studying intelligence are necessary to determine if there are any cognitive features of this condition.

The symptoms and physical findings associated with PKAN gene mutations can be distinguished between classical and atypical disease. Individuals with classical disease have a more rapid progression of symptoms. In most cases, atypical disease progresses slowly over several years. The symptoms and physical findings vary from case to case.

Classical PKAN develops in the first ten years of life (average age for developing symptoms is three and a half years). These children may initially be perceived as clumsy and later develop more noticeable problems with walking. Speech delay is also common. Eventually, falling becomes a frequent feature. Because of the limited ability to protect themselves during falls, children may have repeated injury to the face and chin. Many individuals with the classic form of PKAN require a wheelchair by their mid-teens (in some cases earlier). Most lose the ability to move/walk independently between 10 and15 years after the beginning of symptoms.

Individuals with classical PKAN are more likely to have specific eye problems. Approximately two-thirds of these patients will have retinal degeneration. This is a progressive degeneration of the nerve-rich membrane lining the eyes (retina), resulting in tunnel vision, night blindness, and loss of peripheral vision. Loss of this peripheral vision may contribute to the more frequent falls and gait disturbances in the early stages. [For more information on this retinopathy (retinitis pigmentosa), choose “retinitis pigmentosa” as your search term in the Rare Disease Database].

The atypical form of PKAN usually occurs after the age of ten years and progresses more slowly. The average age for developing symptoms is 13 years. Loss of independent ambulation (walking) often occurs 15 to 40 years after the initial development of symptoms. The initial presenting symptoms usually involve speech. Common speech problems are repetition of words or phrases (palilalia), rapid speech (tachylalia), and dysarthria. Psychiatric symptoms are more commonly observed and include impulsive behavior, violent outbursts, depression, or a tendency to rapid mood swings. While the movement disorder is a very common feature, it usually develops later. In general, atypical disease is less severe and more slowly progressive than early-onset PKAN.

In cases of neurodegeneration with brain iron accumulation (NBIA) that are not caused by PKAN, the movement-related symptoms (such as dystonia) may be very similar. Nine additional genes causing various subtypes of NBIA have been identified at this time. For those without a specific diagnosis or known cause of NBIA, symptoms are more varied because there are probably several different causes of neurodegeneration in this group. There is a subgroup of patients with moderate to severe intellectual disability. Also, seizure disorders are more common among non-PKAN individuals.

Causes

Individuals with PKAN have abnormal accumulation of iron in certain areas of the brain. This is especially seen in regions of the basal ganglia called the globus pallidus and the substantia nigra. The basal ganglia is a collection of structures deep within the base of the brain that assist in regulating movements. The exact relationship between iron accumulation and the symptoms of PKAN is not fully understood.

PKAN is an autosomal recessive condition caused by mutations in the PANK2 gene, located on chromosome 20. This gene encodes the enzyme pantothenate kinase, and mutations in the gene lead to an inborn error of vitamin B5 (pantothenate) metabolism. Vitamin B5 is required for the production of coenzyme A in cells. Disruption of this enzyme affects energy and lipid metabolism and may lead to accumulation of potentially harmful compounds in the brain, including iron. Currently, PANK2 is the only gene known to be associated with PKAN.

Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.

All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. Consanguinity is thought to be present in approximately 23% of families with PKAN.

Affected Populations

PKAN affects males and females in equal numbers. The symptoms typically develop during childhood, although occasionally they begin during late adolescence or adulthood. Cases in infancy and of adult onset have also been reported.

The frequency of PKAN is estimated to be one to three per million individuals worldwide. Because rare disorders like PKAN often go unrecognized, these disorders may be under-diagnosed or misdiagnosed, making it difficult to determine the accuracy of these estimates.

Related Disorders

Symptoms of the following disorders can be similar to those of PKAN. Comparisons may be useful for a differential diagnosis.

The following three disorders may present with early clinical symptoms that are similar to those seen in classic PKAN:

Infantile neuroaxonal dystrophy (INAD), also known as Seitelberger disease, is an extremely rare inherited degenerative disorder of the nervous system characterized by abnormalities of nerve endings (axons) within the brain and spinal cord (central nervous system) and outside the central nervous system (peripheral nerves). In most cases, infants and children with Seitelberger disease appear to develop normally until approximately 14 to 18 months of age, when they may begin to experience progressively increased difficulties in walking. In other cases, symptoms may begin at approximately six to eight months of age, at which time infants may experience delays or an arrest in the acquisition of skills requiring the coordination of mental and physical activities (delayed psychomotor development). Affected infants and children may then begin to lose previously acquired skills (psychomotor regression) including sitting and standing and may demonstrate progressive neuromuscular impairment characterized by generalized muscle weakness, severely diminished muscle tone (hypotonia), abnormally exaggerated reflex responses (hyperreflexia), and/or unusually weak, depressed, or absent reflexes. In some cases, as the disorder progresses, affected children may also experience involuntary movements of the face and hands, sudden involuntary muscle spasms (spasticity) of the lower arms and legs (limbs), and progressive paralysis of the legs and lower part of the body (paraplegia). Progressive cognitive failure occurs in association with gradual motor impairment. In most cases, Seitelberger disease is inherited as an autosomal recessive trait. (For more information on this disorder, choose “Seitelberger” as your search term in the Rare Disease Database.)

Fucosidosis is a rare genetic disorder characterized by deficiency of the enzyme alpha-L-fucosidase, which is required to break down (metabolize) certain complex compounds (e.g., fucose-containing glycolipids or fucose-containing glycoproteins). Fucose is a type of the sugar required by the body to perform certain functions (essential sugar). The inability to breakdown fucose-containing compounds results in their accumulation in various tissues in the body. Fucosidosis results in progressive neurological deterioration, skin abnormalities, growth retardation, skeletal disease and coarsening of facial features. The symptoms and severity of fucosidosis are highly variable and the disorder represents a disease spectrum in which individuals with mild cases have been known to live into the third or fourth decades. Individuals with severe cases of fucosidosis can develop life-threatening complications early in childhood.

Other disorders to be considered in a differential diagnosis include:

Wilson’s disease is a rare genetic disorder characterized by excess copper stored in various body tissues, particularly the liver, brain, and corneas of the eyes. The disease is progressive and, if left untreated, it may cause liver (hepatic) disease, central nervous system dysfunction, and death. Early diagnosis and treatment may prevent serious long-term disability and life threatening complications. Treatment is aimed at reducing the amount of copper that has accumulated in the body and maintaining normal copper levels thereafter. (For more information on this disorder, choose “Wilson’s” as your search term in the Rare Disease Database.)

Batten disease, a rare genetic disorder, belongs to a group of progressive degenerative neurometabolic disorders known as the neuronal ceroid lipofuscinoses. These disorders share certain similar symptoms and are distinguished in part by the age at which such symptoms appear. Batten disease is sometimes considered the juvenile form of the neuronal ceroid lipofuscinoses (NCLs). The NCLs are characterized by abnormal accumulation of certain fatty, granular substances (i.e., pigmented lipids [lipopigments] ceroid and lipofuscin) within nerve cells (neurons) of the brain as well as other tissues of the body that may result in progressive deterioration (atrophy) of certain areas of the brain, neurological impairment, and other characteristic symptoms and physical findings. (For more information on this disorder, choose “Batten” as your search term in the Rare Disease Database.)

Neuroacanthocytosis is a general term for a group of rare progressive disorders characterized by the association of misshapen, spiny red blood cells (acanthocytosis) and neurological abnormalities, especially movement disorders. Chorea, which is characterized by rapid, involuntary, purposeless movements, especially of the face, feet and hands, is the most common movement disorder associated with neuroacanthocytosis. Additional symptoms often develop including progressive cognitive impairment, muscle weakness, seizures and behavioral or personality changes. The onset, severity and specific physical findings vary depending upon the specific type of neuroacanthocytosis present. Neuroacanthocytosis syndromes typically progress to cause serious, disabling and sometimes life-threatening complications (and are usually fatal). (For more information on this disorder, choose “neuroacanthocytosis” as your search term in the Rare Disease Database.)

Parkinson disease is a slowly progressive neurologic condition characterized by involuntary trembling (tremor), muscular stiffness or inflexibility (rigidity), slowness of movement and difficulty carrying out voluntary movements. Degenerative changes occur in areas deep within the brain (substantia nigra and other pigmented regions of the brain), causing a decrease in dopamine levels in the brain. Dopamine is a neurotransmitter, which is a chemical that sends a signal in the brain. Parkinsonian symptoms can also develop secondary to hydrocephalus (a condition in which the head is enlarged and areas of the brain accumulate excessive fluids, resulting in an increase in pressure on the brain), head trauma, inflammation of the brain (encephalitis), obstructions (infarcts) or tumors deep within the cerebral hemispheres and the upper brain stem (basal ganglia), or exposure to certain drugs and toxins. Parkinson’s disease is slowly progressive and may not become incapacitating for many years. (For more information on this disorder, choose “Parkinson’s” as your search term in the Rare Disease Database.)

Huntington’s disease is a genetic, progressive, neurodegenerative disorder characterized by the gradual development of involuntary muscle movements affecting the hands, feet, face, and trunk and progressive deterioration of cognitive processes and memory (dementia). Neurologic movement abnormalities may include uncontrolled, irregular, rapid, jerky movements (chorea) and athetosis, a condition characterized by relatively slow, writhing involuntary movements. Dementia is typically associated with progressive disorientation and confusion, personality disintegration, impairment of memory control, restlessness, agitation, and other symptoms and findings. In individuals with the disorder, disease duration may range from approximately 10 years up to 25 years or more. Life-threatening complications may result from pneumonia or other infections, injuries related to falls, or other associated developments. Huntington’s disease is inherited as an autosomal dominant trait. (For more information on this disorder, choose “Huntington” as your search term in the Rare Disease Database.)

Machado-Joseph disease is a rare inherited disorder affecting the central nervous system that is characterized by the slow degeneration of certain areas of the brain. Symptoms typically begin during adulthood and may include an unsteady gait (ataxia), dysarthria, muscle rigidity, impaired muscle tone, slow involuntary movements of the arms and legs (athetosis), and/or irregular eye movements. Mental alertness and intellectual capacities are not affected. This disorder primarily affects people of Portuguese heritage. Joseph’s disease is inherited as an autosomal dominant trait. (For more information on this disorder, choose “Joseph” as your search term in the Rare Disease Database.)

Certain rare metabolic disorders can also present with symptoms similar to PKAN, including beta-hexosaminidase deficiency disorders such as Tay-Sachs disease and Sandhoff disease. (For more information on these disorders, choose “Tay-Sachs” or “Sandhoff ” as your search term in the Rare Disease Database.)

Diagnosis

The diagnosis of PKAN is made based upon a detailed patient history, a thorough clinical evaluation, and a variety of specialized tests. PKAN is typically suspected when the characteristic brain MRI finding called the “eye-of-the-tiger” sign, which is a dark area indicating accumulation of iron with a bright spot in the center, is observed on T2-weighted MRI. This MRI finding is not seen in other forms of NBIA.

Molecular genetic testing for the full gene sequence of the PANK2 gene is the gold standard way to make this diagnosis. Approximately 95% of those affected have two identifiable mutations in this gene and approximately 5% have only one identifiable mutation. Some PANK2 gene deletions are not detected by sequencing the gene, so for individuals without a detectable mutation or only one detectable mutation, gene deletion/duplication analysis is also recommended.

Clinical Testing and Work-Up

Neurologic examination for dystonia, rigidity, choreoathetsis, spasticity and speech should be conducted. Ophthalmologic examination for retinopathy is also appropriate. Developmental screening and assessment for physical, occupational and speech therapy may also be done.

Standard Therapies

Treatment

There is no specific treatment for individuals with PKAN. Treatment is directed towards the specific symptoms that appear in each individual. Research is focusing on a better understanding of the underlying cause of this disorder, which may eventually help to find a more comprehensive treatment.

Treatment may require the coordinated efforts of a team of specialists. Physicians that the family may work with include the pediatrician or internist, neurologist, ophthalmologist, physiatrist and geneticist. A team approach to supportive therapy may include physical therapy, exercise physiology, occupation therapy, speech pathology and nutrition/feeding. In addition, many families may benefit from genetic counseling.

The most consistent forms of relief from disabling dystonia are baclofen, trihexyphenidyl, and clonazepam. These medications can be taken orally. Later in disease, a baclofen pump can be used to administer regular doses automatically into the central nervous system. Intramuscular botulinum toxin may also help treat specific regions where dystonia is problematic.

Levodopa/carbidopa does not generally appear to help patients with PKAN, although there may be exceptions. These treatments may have a role in the treatment of other causes of NBIA; however, their overall effectiveness is unknown and the responsiveness in individual cases is unpredictable.

Drugs that reduce the levels of iron in the body (iron chelation) have been attempted to treat individuals with PKAN. These early agents were proven ineffective and can cause anemia. Newer forms of chelation therapy, including the drug deferiprone, are being studied to determine if they could be beneficial (see www.clinicaltrials.gov).

Pallidotomy and thalamotomy have been investigational attempts at controlling dystonia. These are both surgical techniques which destroy (ablate) very specific regions of the brain, the pallidus and thalamus, respectively. Some families have reported some immediate and temporary relief. However, most patients return to their pre-operative level of dystonia within one year of the operation. Deep brain stimulation of the globus pallidus has been found to have promising results in some patients with PKAN and NBIA.

Individuals experiencing seizures usually benefit from standard anti-convulsive drugs. In addition, standard approaches to pain management are generally recommended where there is no identifiable treatment for the underlying cause of pain. Referral to pediatric palliative care specialists can be highly beneficial during later disease stages.

The association between pantothenate kinase and PKAN suggests that supplemental pantothenate (pantothenic acid, calcium pantothenate) taken orally could be beneficial. Pantothenate is another name for vitamin B5, a water soluble vitamin. Theoretically, this is most likely to assist individuals with very low levels of pantothenatee kinase activity (atypical PKAN). It is hypothesized that classic PKAN results from complete absence of the enzyme pantothenate kinase, whereas atypical PKAN results from a severe deficiency, although the individuals still may have some level of enzyme activity. Clinical trials are needed to investigate the effectiveness of this treatment.

The benefits and limitations of any of the above treatments should be discussed in detail with a physician.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov . All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222

TTY: (866) 411-1010

Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:

Years Published

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